This proposal seeks to renew a fruitful 5-year Midcareer Award in Clinical Research. The prior funding period permitted the mentoring of 11 junior faculty members, 11 Fellows, and four medical students and residents. The PI was able to recruit two new junior faculty members and assist in the obtainment of three successful career development grant awards and one start up grant for a junior faculty member. Over nine peer reviewed manuscripts and 23 total publications have resulted. The PI's current funding includes a NIH funded investigator-initiated R21, a multicenter U10 grant, a private industry funded supplement to the R21grant, and a private foundation funded multicenter randomized, clinical trial. All of these ongoing projects form a potential nidus for research for interested junior investigators, Fellows, Residents and medical students. The mentorship plans for all of these potential projects are further developed in Aim 1. As proposed in the initial grant application, a new line of investigation into the factors responsible for the maturation of the hypothalamic-pituitary-ovarian axis in pubertal girls has been initiated, and the early findings inspire continued research focused on better understanding the chronology and key determinants of menarche and attainment of ovulatory capacity in girls traversing puberty. Based upon these initial findings, we propose two specific aims relevant to this research: Aim 2, to test the hypothesis that the positive endocrine feedback response to estradiol is typically present before menarche, we will administer a brief estradiol challenge to 10 girls in the early, mid and late stages of puberty and assess the hypothalamic-pituitary response to the intervention. Aim 3, to test the hypothesis that nutritional signals from adipose tissue are key regulators of the endocrine milestones of puberty, we will correlate the key nutritional and auxological signals, leptin, adiponectin, ghrelin, and the circulating growth factor IGF-1 and its binding proteins with pubertal stage, menarcheal age and self reported menstrual history in a sample of 62 girls in various stages of the pubertal transition. Achievement of the aims of this project hold promise to shed new light on the normal pubertal process in young women. These findings, in turn, are expected to be applied to improved diagnosis and early intervention of reproductive abnormalities in young women. In the process of acquiring this information, the long-term academic goals of teaching and training will be accomplished for both the PI and for her prot[unreadable]g[unreadable]s.